SUMMARY Base excision repair (BER) is a major pathway that functions to maintain genome stability. During the past few years many human germline and tumor genomes have been sequenced, resulting in the identification of mutations in a number of genes including those that function in BER. However, little is known about these mutations because many of them are rare, precluding population-based genetic studies. The rationale is that functional characterization of these germline and somatic variants will provide important insights into their functions with specific regard to human cancer. The broad, long-term objectives of the proposed research are to determine if there is a link between the presence of variants in the BER genes and human cancer. The other objective is to determine if and how mutations in these genes impact cancer therapy. The specific aims are 1) To test the hypothesis that human germline and somatic variants of the NEIL1, 2, 3, NTHL1 and OGG1 DNA glycosylases exhibit functional phenotypes related to the etiology of human cancer; 2) To test the hypothesis that germline and somatic variants of the human DNA glycosylases NEIL1, 2, 3, NTHL1, and OGG1 have the potential to impact cancer treatment. Core A, in collaboration with the other projects, will identify variants for functional characterization. Project 1 will characterize variants that exhibit functional and/or structural defects identified in Projects 2, 3, and 4. A combined genetics and cell biology approach will be used to characterize these variants and assess their ability to induce genomic instability, cellular transformation, and to impact responses to chemotherapies. Project 1 will also participate in the characterization of the biological phenotypes of mutants produced in Project 4.